Methods and systems for modifying vascular valves

ABSTRACT

Described are methods and systems for modifying vascular valves in order to reduce retrograde blood flow through the valves. Preferred methods include connecting vascular valve leaflets with at least one remodelable material, such that the valve leaflets become fused by the ingrowth of the patient&#39;s native tissue. Preferred remodelable materials include collagenous extracellular matrix material, such as small intestine submucosa.

STATEMENT OF RELATED APPLICATIONS

This application claims the benefit of priority of U.S. ProvisionalPatent Application Ser. No. 60/622,765 filed Oct. 28, 2004 which isincorporated herein by reference in its entirety.

BACKGROUND

The present invention relates generally to a method for modifyingvascular valves. One aspect of the present invention provides a methodfor modifying the leaflets of one or more venous valves with anextracellular matrix (ECM) material in order to enhance the valve orvalves.

As further background, vascular vessels are comprised of tissue and arethe conduit for circulating blood through a mammalian body. A vascularvessel that carries blood from the heart is known as an artery. Avascular vessel that returns blood to the heart is known as a vein.There are three types of veins in a human: deep veins, which are locateddeep in the body close to the bones, superficial veins, which arelocated close to the skin, and perforating veins, which are smallerveins that connect the deep veins to the superficial veins.

To assist blood flow, venous vascular vessels contain venous valves.Each venous valve is located inside the vein and typically includes atleast two valve leaflets, which are disposed annularly along the insidewall of the vein. These leaflets open to permit blood flow toward theheart and close, upon a change in pressure, to restrict the back flow ofblood. When blood flows towards the heart, the venous pressure forcesthe valve leaflets to move apart in a downstream flexing motion, therebycreating an open path for blood flow. The leaflets normally flextogether when moving in the upstream direction; therefore, they returnto a closed position to restrict or prevent blood flow in the upstream,or retrograde, direction after the venous pressure is relieved. Theleaflets, when functioning properly, extend radially inward toward oneanother such that the leaflet tips, or cusps contact each other when thevalve is closed.

On occasion, and for a variety of reasons, such as congenital valve orvein weakness, disease in the vein, obesity, pregnancy, and/or anoccupation requiring long periods of standing, one or more valves in avein will allow deleterious retrograde flow to occur. When a valveallows such retrograde flow, blood will collect, or pool in vesselsbelow the valve. This pooling of blood causes an increase in the venouspressure beneath the valve. Venous valves that allow such deleteriousretrograde flow are known as incompetent or inadequate venous valves.The condition resulting from such incompetent venous valves is known asvenous valve insufficiency.

In the condition of venous valve insufficiency, the venous valveleaflets do not function properly. Incompetent venous valves can causethe veins to bulge, can cause swelling in the patient's lowerextremities, and can result in varicose veins and/or chronic venousinsufficiency. If left untreated, venous valve insufficiency can causevenous stasis ulcers of the skin and subcutaneous tissue.

A common method of treatment for venous valve insufficiency is theplacement of an elastic stocking around the patient's leg to applyexternal pressure to the vein, forcing the walls radially inward toforce the leaflets into apposition. Although sometimes successful, thetight stocking is quite uncomfortable, especially in warm weather,because the stocking must be constantly worn to keep the leaflets inapposition. The elastic stocking also affects the patient's physicalappearance, thereby potentially having an adverse psychological affect.This physical and/or psychological discomfort can lead to the patientremoving the stocking, thereby inhibiting treatment.

Surgical methods for treatment of venous valve insufficiency have alsobeen developed. A vein with incompetent venous valves can be surgicallyconstricted to bring incompetent leaflets into closer proximity in hopesof restoring natural valve function. Methods for surgical constrictionof an incompetent vein include implanting a frame around the outside ofthe vessel, placing a constricting suture around the vessel (e.g.,valvuloplasty), or other types of treatment to the outside of the vesselto induce vessel contraction. Other surgical venous valve insufficiencytreatment methods include bypassing or replacing damaged venous valveswith autologous sections of veins containing competent valves.

Another surgical method includes vein stripping and ligation. In thisprocedure, the femoral vein and other major venous tributaries aredisconnected from the greater saphenous vein and tied off. Next, thegreater saphenous vein is removed from the leg by advancing a wirethrough the vein, tying the wire to a saphenous vein end, and thenpulling the wire, and vein, out through an incision in the upper calf orankle. Unfortunately, the above surgeries require at least one incision,and have several undesirable side effects and risks, such as a longpatient recovery time, the potential for scarring, and numerous otherrisks inherent with surgery, such as those associated withadministration of anesthesia.

Recently, various implantable prosthetic devices and minimally invasivemethods for implantation of these devices have been suggested to treatvenous valve insufficiency. Such prosthetic devices can be insertedintravascularly, for example from an implantation catheter. Prostheticdevices can function as a replacement venous valve, or enhance venousvalve function by bringing incompetent valve leaflets into closerproximity. In one procedure, venous valve function can be enhanced byclipping the valve leaflets together with a clip made from abiocompatible material, such as a metal, polymer, or fabric. In otherprocedures, venous valve leaflets can be attached using a plastic ormetal staple.

Recently, a number of methods have been suggested to treat varicoseveins and venous valve leaflets with energy sources, such asradiofrequency (RF) energy. In one such method, valve leaflets can befastened together with electrodes delivering RF energy. In another suchmethod, a catheter having an electrode tip can be used to apply RFenergy to cause localized heating and corresponding shrinkage of venoustissue. After treatment of one venous section is complete, the cathetercan be repositioned to treat a different venous section.

Methods for treatment of varicose veins have also been developedinvolving various forms of sclerotherapy. Generally, sclerotherapyinvolves the delivery of one or more sclerosing agents to the lumen of avein, which induce the vein to collapse and the venous walls to fuse,thereby closing the vein.

In view of the above background, the need remains for improved andalternative methods and systems for affecting the venous system to treatvenous conditions. The present invention is addressed to these needs.

SUMMARY

In one aspect, the invention relates to surgical methods for modifyingvascular valves. The surgical methods include the modification of valveleaflets with a remodelable material. Advantageous such remodelablematerials include extracellular matrix (ECM) material, such as mammaliansmall intestine submucosa.

In another aspect, the invention provides a method for modifying avascular valve in a patient that includes connecting at least two valveleaflets of a vascular valve in at least one location with a remodelablematerial, so as to promote tissue of the patient to remodel and connector fuse the leaflets. In certain aspects, the remodelable material caninclude an extracellular matrix material, such as mammalian porcinesubmucosa.

In another aspect, the invention provides a method for modulating theflow of blood in a vascular vessel that includes connecting together aregion of at least two valve leaflets in a vascular valve with anextracellular matrix material. In certain aspects, the extracellularmatrix material can comprise one or more sutures.

In yet another aspect, the invention provides a valve modificationmethod that includes clipping venous valve leaflets together with a clipcomprising a remodelable material in a manner such that the clipencourages remodeling, thereby causing the valve leaflets to fuse withpatient tissue.

In yet another aspect, the invention provides a method for treating avenous insufficiency in a leg of a patient that includes connecting afirst valve leaflet in a venous valve to a second valve leaflet in thevenous valve with at least one bioremodelable material, so as to promotetissue of the patient to remodel the bioremodelable material to connectthe first valve leaflet to the second valve leaflet. In certain aspects,the bioremodelable material is a clip for connecting the valve leaflets.

In another aspect, the invention provides a valve modification methodinvolving positioning a remodelable material between two venous valveleaflets, followed by inserting a connector such as a staple through theleaflets and the remodelable material, such that the remodelablematerial causes the valve leaflets to fuse with patient tissue.

In yet other aspects, the invention provides systems for percutaneouslymodifying a valve or valves in a vascular vessel with a remodelablematerial.

The present invention provides improved and/or alternative methods andsystems for modifying vascular valves. Additional embodiments andfeatures and advantages of the invention will be apparent from thedescriptions herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective view, in partial cross-section, showing avascular vessel having both adequate and inadequate valves.

FIG. 2 is a perspective view taken along line 2-2 in FIG. 1 showing anadequate bicuspid vascular valve.

FIG. 3 is a perspective view taken along line 3-3 in FIG. 1 showing aninadequate bicuspid vascular valve.

FIG. 4 is a perspective view, in partial cross-section, showing aninadequate bicuspid vascular valve.

FIG. 5 is a perspective view, in partial cross-section, showing abicuspid vascular valve that has been modified with a remodelable and/orbioabsorbable material.

FIG. 6 is a perspective cross-sectional view of a vascular vesselshowing a bicuspid valve modified in one location with a remodelableand/or bioabsorbable material.

FIG. 7 is a perspective cross-sectional view of a vascular vesselshowing a bicuspid valve modified in two locations with remodelableand/or bioabsorbable materials.

FIG. 8 is a perspective cross-sectional view of a vascular vesselshowing a remodeled bicuspid vascular valve of the present invention.

FIG. 9 is a perspective cross-sectional view of a vascular vesselshowing a remodeled bicuspid vascular valve of the present invention.

DETAILED DESCRIPTION

For the purposes of promoting an understanding of the principles of theinvention, reference will now be made to certain embodiments thereof andspecific language will be used to describe the same. It willnevertheless be understood that no limitation of the scope of theinvention is thereby intended, such alterations, further modificationsand further applications of the principles of the invention as describedherein being contemplated as would normally occur to one skilled in theart to which the invention relates.

As disclosed above, the present invention provides methods that includemodifying a vascular valve by attachment of a remodelable material tothe valve, such that the remodelable material promotes in-growth ofpatient tissue into the remodelable material and modifies the functionof the valve. The invention also provides methods of deliveringremodelable and/or bioabsorbable material to vascular valves, as well asmethods of securing remodelable material to vascular valve leaflets.

Turning now to a discussion of venous valves, depending on the stage andseverity of venous valve insufficiency, several modes of venous valvefailure can exist in one or more valves in one or more vein. Forexample, in a distended vein, the leaflets may allow undesirable ordeleterious retrograde flow because the leaflet cusps no longerproximately locate one another when the valve is in its closed position.Alternatively, one or more valve leaflets may tear, causing only aportion of a leaflet cusp or leaflet to allow undesirable retrogradeflow. Still alternatively, one or more leaflets may degenerate to thepoint that the leaflets or a portion of the leaflets fail to proximatelylocate in order to prevent deleterious back flow.

As shown in FIG. 1, more than one venous valve may become inadequate inthe same vein. FIG. 1 depicts a portion of a vein 10 containing twoinadequate venous valves 7, 15 and three adequate venous valves 5, 15,17. The venous valves in FIG. 1 are bicuspid valves, each having twovalve leaflets, exemplified in valve 5 by numerals 25 and 26. In anadequate venous valve 17, each leaflet 25, 26 extends into the vein 10lumen and projects downstream A toward the heart. In so doing, eachleaflet defines a reservoir 30, which collects blood during retrogradeflow forcing each valve leaflet 25, 26 to close. FIG. 2, a crosssectional view taken along line 2-2 in FIG. 1, depicts an adequatevenous valve 17 in its closed position. As shown, the lip 35, 36 of eachleaflet is located proximate one another in order to prevent undesirableretrograde blood flow.

For a number of reasons, as discussed above, the valve leaflets 27, 28in an inadequate valve 7 may fail to prevent deleterious retrogradeblood flow. When this occurs, at least a portion of the leaflet cusps37, 38 fail to sufficiently locate proximate one another to prevent theundesirable back flow of blood. One mode of valve failure is displayedin FIG. 4, which shows a cross-section of inadequate valve 7 taken alongthe valve's vertical centerline. In FIG. 4, it is apparent that thevalve cusps or lips 37, 38 do not sufficiently locate at the center orother points along each valve leaflet 27, 28 to adequately preventundesirable retrograde blood flow. Another mode of valve failure isdisplayed in FIG. 3, which depicts a horizontal cross-section takenalong line 3-3 in FIG. 1. In FIG. 3, it is apparent that valve cusps 37,38 do not sufficiently locate across substantially the entire lumen ofvessel 10 to adequately prevent deleterious retrograde blood flow.Alternatively, the cusps in an inadequate valve may fail to sufficientlylocate at any one or more locations across the vessel lumen toadequately prevent undesirable retrograde blood flow, or a tear oraperture may be present in at least one of the valve leaflets 27, 28thereby allowing deleterious retrograde flow to occur.

In certain embodiments, a surgical method can include connecting valveleaflets 37, 38 in an inadequate valve 7 with a remodelable material inorder to reduce the quantity of retrograde blood flow through thatvalve. As discussed below, the remodelable material will promoteremodeling such that the patient's tissue grows within or into theremodelable material.

Illustratively, a surgical method can include a venous catheterization.Access can be established at a location proximate the patient's ankle,or, alternatively, access may be obtained at any suitable location onthe patient's body, such as the neck or knee. In alternativeembodiments, access can be established surgically, by performing acutdown, or other suitable surgical method, to the appropriate vein inany suitable location.

After access is achieved, a remodelable material can be delivered to aninadequate valve. Delivery of the remodelable material to the inadequatevalve can be achieved in any suitable manner, a number of which areknown in the art. One such delivery method involves delivery of theremodelable material with a catheter. For example, the material can beplaced and held on the distal tip of a gripper, operated by eithersuction or mechanical means, e.g. claws, and then delivered to theinadequate valve by pushing the gripper and material through thecatheter to the valve. For additional information concerningpercutaneous delivery and positioning of material, reference can bemade, for example, to U.S. Pat./application Nos. 5,609,598, 5,810,847,6,149,660, 6,575,971, 6,695,866, 2003/0093071, and/or 2004/0167539.

After delivery to the target site, the remodelable material can besecured to pertinent valve leaflets with a suitable securing deviceand/or method. For example, the material can be secured using one ormore sutures, staples, and/or temporary or permanent clamps, clips, orbarbs. If a temporary securing method is used, the device can optionallybe percutaneously or surgically retrieved at a later time, oroptionally, the device can be made of a bioremodelable and/orbioabsorbable material, such that retrieval is not necessary for removalof the device. In additional embodiments, the remodelable material canbe fashioned into a clip, clamp, and/or barb, which is then used toconnect or bring together the valve leaflets and promote fusion of thevalve leaflets with patient tissue. As such, delivery and placement ofthe clamp, clip, and/or barb can occur using an instrument, such as acatheter, which can optionally contain multiple clamps, clips, and/orbarbs for deployment within the vasculature. Still alternatively, aremodelable material may be incorporated in a gel or glue that iscontacted with the valve leaflets which are brought into contact withand held against each other, e.g. with a suture, clip or clamp and/or bythe bonding function of the gel or glue. Yet still alternatively, inadditional embodiments, the remodelable material can comprise athree-dimensional shape that is placed between the leaflets and issecured using a staple or suture, for example a suture made from an ECMmaterial.

Multiple techniques are known in the art to suture, staple, and/or clipor fasten tissue percutaneously. For example, a catheter including agripper with a mechanical claw can be used to place a clip or barb ontoor through valve leaflets. Alternatively, a mechanized suturing devicecan be inserted through a catheter and delivered to the valve leafletsin order to suture material to each leaflet, or alternatively, suturethe leaflets together. Still alternatively, a stapling device can beattached to the end of a catheter and positioned adjacent to the valveleaflets in order to secure material to those leaflets. For additionalinformation as to clipping, suturing, and/or stapling techniques usefulin the present invention, reference can be made, for example, to U.S.Pat. Nos. 5,609,598, 5,584,861, 5,810,847, 6,149,660, 6,695,866,6,575,971, and/or European Patent Application EP 442,588, and/or GreatBritain Patent Application GB2,165,559. Still further, energy-driventissue welding or bonding techniques can be used in combination withsolid or flowable ECM materials to attach one or more portions of theleaflets together such that remodeling promoted by the ECM materialfuses the leaflets together. For example, an amount of ECM material canbe positioned between leaflet portions in location(s) wherepatient-tissue-fusion is desired, and two or more energy-delivering(e.g., RF delivering) probes can be used to force the leaflets againstthe inner piece or amount of ECM material. The probes can then be usedto deliver energy and fuse or bond each leaflet to a respective side orlocation of the ECM material. Afterward, the ECM material will promoteremodeled fusion of the targeted leaflet location(s).

Valve modification can be performed on any one or more vascular valve inany one or more vein or artery as is suitable. In a vein with more thanone inadequate valve, the valve located furthest from access can be thefirst valve modified. In FIG. 1, for example, in certain embodiments,access can be obtained upstream of both inadequate valves 7, 15. Inthese embodiments, the inadequate venous valve 15 located furthestdownstream can be modified before the more upstream inadequate venousvalve 7. In alternative embodiments, access can be obtained downstreamof both inadequate valves 7, 15. In these embodiments, the inadequatevalve 7 located furthest upstream can be modified before the moredownstream valve 15. Alternatively, in other embodiments, inadequatevenous valves in a common vein can be modified in any suitable order.

When modifying multiple valves in a common vessel, the remodelable orbioabsorbable material, whether it be in the form of a device, such as aclip, layer, and/or gel, can be delivered on an as needed basis or,alternatively, multiple materials can be stored in the delivery device.For example, in embodiments where material is delivered on an as-neededbasis, the delivery device, i.e. gripper, can be removed from thecatheter after material delivery, reloaded with new material, and thenre-inserted into the catheter as more material is needed. Alternatively,if a delivery device or catheter containing multiple materials is used,the device does not need to be removed from the vasculature in betweenvalve modifications.

With reference now to FIGS. 5 and 6, illustratively, a venous valve canbe modified by securing a remodelable and/or bioabsorbable material 40to the leaflets 27, 28 of an inadequate venous valve 45. As depicted inFIG. 6, the material 40 can be first secured to valve leaflet 27, and orlip 37, and then secured to leaflet 28, and or cusp 38, in a manner suchthat the open space between leaflets 27 and 28 is reduced. The material40 can be secured to the leaflets 27, 28 using any suitable securingmethod discussed above, such as sutures, staples, clips, and/or bondingagents. In certain embodiments, sutures made from a remodelablematerial, such as an ECM material, discussed in more detail below, canbe used. In alternative embodiments, a material and both leaflets can besimultaneously secured together with one or more suture, staple, and/orclip, such as a bioabsorbable staple or clip. For example, a material,in solid or gel form, can be placed in between the leaflets and securedfor instance by inserting a connector such as a staple, barb, and/orsuture through both leaflets and the material or holding the leafletstogether by a device such as a clip or clamp. In still alternativeembodiments, the leaflets can be modified by suturing portions orregions of them together with a remodelable suture, such as a suturemade from an ECM material, such as small intestine submucosa.

As is illustratively shown in FIG. 6, the remodelable and/orbioabsorbable material 40 can be placed approximately along the centralaxis of the venous lumen. However, in other embodiments, the materialcan be placed in any suitable location or locations along the valveleaflets. For example, FIG. 7 depicts an embodiment where two materials50, 55 are used to modify a venous valve. Either one or both materials50, 55 can be a remodelable material or a bioabsorbable material or anysuitable combination thereof.

Turning now to FIG. 8, the modified valve of FIG. 6 is shown after aperiod of time sufficient to allow the patient's tissue to remodel theremodelable and/or bioabsorbable material 40. As shown in FIG. 8, theremodelable material 40 has been replaced with the patient's nativetissue 60 in such a manner as to sufficiently maintain the valveleaflets 27, 28 and cusps 37, 38 in their modified position.

Additionally, as shown in FIG. 9, the valve leaflets 27, 28 can bemodified in a location approximate the junction of each valve leaflet27, 28 with the vessel wall 65. The valve in FIG. 9 is shown in itsremodeled state, such that the patient's native tissue 60 is maintainingthe valve 45 in its modified form.

Valve modification can include the use of one or more remodelablematerials, of any suitable shape, size, and/or construction, in anysuitable location or locations along the valve leaflets and/or vesselwall. For example, in certain embodiments, the remodelable material maybe placed between portions of two or more valve leaflets and secured inplace using suitable glue or bonding agents. Alternatively, theremodelable material may be secured to the upstream side of each valveleaflet, or the upstream side of one or more leaflets and the downstreamside of other leaflet(s), as is necessary. Still alternatively, theremodelable material may be secured to the valve leaflets usingelectrodes equipped with an energy source, such as radiofrequency (RF)energy. The surgical methods of this invention can be used to modify anyvascular valve, arterial or venous, monocuspid, bicuspid, tricuspid, orotherwise.

The remodelable materials of the invention can include collagenousextracellular matrix (ECM) materials, such as submucosa, renal capsulemembrane, dura mater, pericardium, serosa, peritoneum, or basementmembrane. The preferred medical graft products of the invention willinclude submucosa, such as submucosa derived from a warm-bloodedvertebrate. Mammalian submucosa materials are preferred. In particular,submucosa materials derived from animals raised for meat or otherproduct production, e.g. pigs, cattle or sheep, will be advantageous.Porcine submucosa provides a particularly preferred material for use inthe present invention, especially porcine small intestine submucosa,more especially porcine small intestine submucosa retainingsubstantially its native cross-linking.

The submucosa or other ECM material can be derived from any suitableorgan or other biological structure, including for example submucosaderived from the alimentary, respiratory, intestinal, urinary or genitaltracts of warm-blooded vertebrates. Submucosa useful in the presentinvention can be obtained by harvesting such tissue sources anddelaminating the submucosa from smooth muscle layers, mucosal layers,and/or other layers occurring in the tissue source. For additionalinformation as to submucosa useful in the present invention, and itsisolation and treatment, reference can be made, for example, to U.S.Pat. Nos. 4,902,508, 5,554,389, 5,993,844, 6,206,931, and 6,099,567.

As prepared, the extracellular matrix material may optionally retaingrowth factors or other bioactive components native to the sourcetissue. For example, the matrix material may include one or more growthfactors such as basic fibroblast growth factor (FGF-2), transforminggrowth factor beta (TGF-beta), epidermal growth factor (EGF), and/orplatelet derived growth factor (PDGF). As well, submucosa or other ECMmaterial of the invention may include other biological materials such asheparin, heparin sulfate, hyaluronic acid, fibronectin and the like.Thus, generally speaking, the ECM material may include a bioactivecomponent that induces, directly or indirectly, a cellular response suchas a change in cell morphology, proliferation, growth, protein or geneexpression. Further, in addition or as an alternative to the inclusionof such native bioactive components, non-native bioactive componentssuch as those synthetically produced by recombinant technology or othermethods, may be incorporated into the ECM material.

ECM material used in the invention is preferably highly purified, forexample, as described in U.S. Pat. No. 6,206,931. Thus, preferredmaterial will exhibit an endotoxin level of less than about 12 endotoxinunits (EU) per gram, more preferably less than about 5 EU per gram, andmost preferably less than about 1 EU per gram. As additionalpreferences, the ECM material may have a bioburden of less than about 1colony forming units (CFU) per gram, more preferably less than about 0.5CFU per gram. Fungus levels are desirably similarly low, for exampleless than about 1 CFU per gram, more preferably less than about 0.5 CFUper gram. Nucleic acid levels are preferably less than about 5 μ g/mg,more preferably less than about 2 μ g/mg, and virus levels arepreferably less than about 50 plate forming units (PFU) per gram, morepreferably less than about 5 PFU per gram. The ECM material used in theinvention is preferably disinfected with an oxidizing agent,particularly a peracid, such as peracetic acid. These and additionalproperties of submucosa taught in U.S. Pat. No. 6,206,931 may becharacteristic of the ECM material used in the present invention.

The remodelable ECM or other material may include one or more radiopaquemarkers or a radiopaque coating or impregnation to assist invisualization of the material during a non-invasive procedure. Forexample, radiopaque substances containing tantalum, barium, iodine, orbismuth, e.g. in powder form, can be coated upon or incorporated withinthe ECM or other remodelable material.

The remodelable material of the invention may also include a syntheticmaterial, such as a bioabsorbable synthetic polymer, such as polylacticacid or polycaprolactone, for example. The remodelable material may alsobe a combination, or hybrid, of ECM material and synthetic material. Forfurther information concerning suitable bioabsorbable syntheticmaterials useful in certain embodiments of the invention, reference canbe made, for example, to U.S. Utility Patent Application titled,“Implantable Frame with Variable Compliance, ” filed on Apr. 11, 2005(“Express Mail” Mailing Label No. EV 327 135 804 US).

It is also possible for an ECM-based remodelable material used in theinvention to comprise a multilaminate ECM material. To form amultilaminate material, two or more ECM segments are stacked, or one ECMsegment is folded over itself at least one time, and then the layers arefused or bonded together using a bonding technique, such as chemicalcross-linking or vacuum pressing during dehydrating conditions.

In accordance with aspects of the invention, an adhesive, glue or otherbonding agent may be used in achieving a bond between ECM layers, and/orECM material and a valve leaflet and/or patient tissue, such as a vesselwall. Suitable bonding agents may include, for example, collagen gels orpastes, gelatin, or other agents including reactive monomers orpolymers, for example cyanoacrylate adhesives. As well, bonding can beachieved or facilitated using chemical cross-linking agents, such asglutaraldehyde, formaldehyde, epoxides, genipin or derivatives thereof,carbodiimide compounds, polyepoxide compounds, or other similar agents.Cross-linking of ECM materials can also be catalyzed by exposing thematrix to UV radiation, by treating the collagen-based matrix withenzymes such as transglutaminase and lysyl oxidase, and byphotocross-linking. The combination of one or more of these withdehydration-induced bonding may also be used.

In accordance with another aspect of the invention, different drying ordehydration methods can be used to fuse ECM portions of thebioremodelable material. In one preferred embodiment, the multiplelayers of ECM material are compressed under dehydrating conditions. Theterm “dehydrating conditions” is defined to include any mechanical orenvironmental condition which promotes or induces the removal of waterfrom the ECM material. To promote dehydration of the compressed ECMmaterial, at leeast one of the two surfaces compressing the matrixstructure can be water permeable. Dehydration of the ECM material canoptionally be further enhanced by applying blotting material, heatingthe matrix structure or blowing air, or other inert gas, across theexterior of the compressing surfaces. One particularly useful method ofdehydration bonding ECM materials is lyophilization, e.g. freeze-dryingor evaporative cooling conditions.

Another method of dehydration bonding comprises pulling a vacuum on theassembly while simultaneously pressing the assembly together. Thismethod is known as vacuum pressing. During vacuum pressing, dehydrationof the ECM materials in forced contact with one another effectivelybonds the materials to one another, even in the absence of other agentsfor achieving a bond, although such agents can be used while also takingadvantage at least in part of the dehydration-induced bonding. Withsufficient compression and dehydration, the ECM materials can be causedto form a generally unitary ECM structure.

It is advantageous in some aspects of the invention to perform dryingoperations under relatively mild temperature exposure conditions thatminimize deleterious effects upon the ECM materials of the invention,for example native collagen structures and potentially bioactivesubstances present. Thus, drying operations conducted with no orsubstantially no duration of exposure to temperatures above human bodytemperature or slightly higher, say, no higher than about 38° C., willpreferably be used in some forms of the present invention. Theseinclude, for example, vacuum pressing operations at less than about 38°C., forced air drying at less than about 38° C., or either of theseprocesses with no active heating—at about room temperature (about 25°C.) or with cooling. Relatively low temperature conditions also, ofcourse, include lyophilization conditions.

In yet still further applications, a remodelable gel can be formed fromfluidized compositions, as illustrated in U.S. Pat. Nos. 5,275,826,5,516,533, 6,206,931, 6,444,229 and/or in International Publication No.W02005020847 (Cook Biotech Incorporated) published Mar. 10, 2005, whichare each hereby incorporated by reference in their entirety. In thisregard, solutions or suspensions of ECM can be prepared by comminutingand/or digesting ECM with a protease (e.g. trypsin or pepsin), for aperiod of time sufficient to solubilize the ECM and form substantially ahomogenous solution. The ECM starting material is desirably comminutedby tearing, cutting, grinding, shearing or the like. Grinding the ECM ina frozen or freeze-dried state is advantageous, although good resultscan be obtained as well by subjecting a suspension of pieces of thesubmucosa to treatment in a high speed blender and dewatering, ifnecessary, by centrifuging and decanting excess waste. The comminutedECM can be dried, for example freeze dried, to form a powder.Thereafter, if desired, the powder can be hydrated, that is, combinedwith water or buffered saline and optionally other pharmaceuticallyacceptable excipients, to form a fluid medical graft composition, e.g.having a viscosity of about 2 to about 300,000 cps at 25° C. The higherviscosity graft compositions can have a gel or paste consistency. Thisgelatinous medical graft composition can be placed between valveleaflets before securing the leaflets together in order to induce theleaflets to grow together.

Additionally, such gelatinous or flowable materials can includesolubilized and/or particulate ECM components, and in preferred formsinclude ECM gels having suspended therein ECM particles, for examplehaving an average particle size of about 50 microns to about 500microns, more preferably about 100 microns to about 400 microns. The ECMparticulate can be added in any suitable amount relative to thesolubilized ECM components, with preferred ECM particulate to ECMsolubilized component weight ratios (based on dry solids) being about0.1:1 to about 200:1, more preferably in the range of 1:1 to about100:1. The inclusion of such ECM particulates in the ultimate gel canserve to provide additional material that can function to providebioactivity to the gel (e.g. itself including FGF-2 and/or other growthfactors or bioactive substances as discussed herein) and/or serve asscaffolding material for tissue ingrowth. Flowable ECM materials canalso be used in conjunction with other occlusive devices as describedherein, or otherwise.

The invention also encompasses medical products or kits, such as aprosthesis device of the invention configured to connect two or morevalve leaflets, or a catheter loaded with at least one such prosthesisdevice sealed within sterile medical packaging. The final, packagedproduct is provided in a sterile condition. This may be achieved, forexample, by gamma, e-beam or other irradiation techniques, ethyleneoxide gas, or any other suitable sterilization technique, and thematerials and other properties of the medical packaging will be selectedaccordingly. The prosthesis device may be packaged wet or after it isdried.

Surgical methods in accordance with the present invention can be used tomodify vascular valves in mammalian patients, including humans.Preferred surgical methods of the invention find particular utility inrepairing venous valves, such as in deep veins or superficial veins. Forexample, surgical methods of the invention are used with preference inthe treatment of venous valve insufficiency.

All publications cited herein are hereby incorporated herein byreference in their entirety as if each had been individuallyincorporated by reference and fully set forth.

While the invention has been illustrated and described in detail in thedrawings and foregoing description, the same is to be considered asillustrative and not restrictive in character, it being understood thatonly the preferred embodiment has been shown and described and that allchanges and modifications that come within the spirit of the inventionare desired to be protected.

1. A method for modifying a vascular valve in a patient, comprising:connecting at least two valve leaflets in a vascular valve in at leastone location with an extracellular matrix material, so as to promotetissue of the patient to remodel and connect said leaflets, wherein saidextracellular matrix material is in the form of a suture.
 2. The methodof claim 1, wherein said extracellular matrix material comprises,submucosa, dura mater, pericardium, renal capsule membrane, or basementmembrane.
 3. The method of claim 2, wherein said submucosa comprisesmammalian submucosa.
 4. The method of claim 3, wherein said mammaliansubmucosa comprises porcine, bovine, or ovine submucosa.
 5. The methodof claim 4, wherein said porcine submucosa comprises adult porcinesubmucosa.
 6. The method of claim 3, wherein said mammalian submucosacomprises intestinal submucosa, stomach submucosa, urinary bladdersubmucosa, or uterine submucosa.
 7. The method of claim 1, wherein saidremodelable material comprises a bioabsorbable synthetic polymer.
 8. Amethod for modifying a vascular valve in a patient, comprising:connecting at least two valve leaflets in a vascular valve in at leastone location with a remodelable material, so as to promote tissue of thepatient to remodel and connect said leaflets, wherein said remodelablematerial is a hybrid of extracellular matrix material and bioabsorbablesynthetic polymer.
 9. A method for modulating the flow of blood in avascular vessel, comprising: connecting together at least two valveleaflets in a vascular valve with an extracellular matrix material,wherein said extracellular matrix material is connected to the center ofeach valve leaflet at least in part by a suture.
 10. The method of claim9, wherein said vascular valve is a venous valve.
 11. The method ofclaim 10, wherein said vascular valve has two valve leaflets.
 12. Themethod of claim 11, wherein said valve leaflets are connected in atleast one location proximate the junction of each valve leaflet to thecommon wall of said vessel.
 13. A method for modulating the flow ofblood in a vascular vessel, comprising: connecting together at least twovalve leaflets in a vascular valve at the center of each leaflet with anextracellular matrix material, wherein said extracellular matrix is amultilaminate sheet of extracellular matrix material.
 14. A method formodulating the flow of blood in a vascular vessel, comprising:connecting together at least two valve leaflets in a vascular valve atthe center of each leaflet with an extracellular matrix material,wherein said extracellular matrix material comprises a twisted band ofmammalian submucosa.
 15. A method for modulating the flow of blood in avascular vessel, comprising: connecting together at least two valveleaflets in a vascular valve at the center of each leaflet with anextracellular matrix material, wherein said extracellular matrixmaterial comprises a gel.
 16. A method for treating a venousinsufficiency in a leg of a patient, comprising: connecting a firstvalve leaflet in a venous valve to a second valve leaflet in the venousvalve with at least one bioremodelable material comprising a gel formextracellular matrix material, wherein said bioremodelable material isplaced between said first valve leaflet and said second valve leafletand is secured with one or more staple, suture, and/or clip, so as topromote tissue of the patient to remodel said bioremodelable material toconnect said first valve leaflet to said second valve leaflet.
 17. Themethod of claim 16, wherein said bioremodelable material is delivered tosaid venous valve with a delivery device.
 18. The method of claim 17,wherein said delivery device comprises a catheter.
 19. The method ofclaim 16, wherein said securing comprises stapling.
 20. The method ofclaim 16, wherein said bioremodelable material is small intestinesubmucosa and said clip comprises an ECM material.
 21. The method ofclaim 16, wherein: said bioremodelable material is delivered to saidvenous valve with a delivery device, said bioremodelable material ispositioned with a positioning device at a first location on said firstvalve leaflet and at a second location on said second valve leaflet; andsaid bioremodelable material is secured to said first valve leaflet atsaid first location and to said second valve leaflet at said secondlocation.
 22. The method of claim 21, wherein said positioning device isa catheter.
 23. The method of claim 21, wherein said bioremodelablematerial is secured at least in part with staples.
 24. A method formodulating the flow of blood in a vascular vessel, comprising:connecting together a region of at least two valve leaflets in avascular valve with an extracellular matrix material, wherein said valveleaflets are connected in at least one location proximate the junctionof each valve leaflet to the common wall of said vessel and wherein saidextracellular matrix is a multilaminate sheet of extracellular matrixmaterial.
 25. A method for modulating the flow of blood in a vascularvessel, comprising: connecting together a region of at least two valveleaflets in a vascular valve with an extracellular matrix material,wherein said valve leaflets are connected in at least one locationproximate the junction of each valve leaflet to the common wall of saidvessel and wherein said extracellular matrix material comprises atwisted band of mammalian submucosa.
 26. A method for modulating theflow of blood in a vascular vessel, comprising: connecting together aregion of at least two valve leaflets in a vascular valve with anextracellular matrix material, wherein said valve leaflets are connectedin at least one location proximate the junction of each valve leaflet tothe common wall of said vessel and wherein said extracellular matrixmaterial comprises a gel.